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STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency.

Zhengjin He·Shishuang Chen·Jinlong Suo·Kai Xia·Mingxian Liu·Jingchuan Ma·Yankai Chu·Chao Wang·Yueru Xie·Wei Jiang·Hui Du·Shiyang Chen·Zhilei Zhou·Man Li·Qing Wei·Yun Zhao·Jianfeng Chen·Lin Li·Yi Zeng·Weiguo Zou·Moubin Lin·Hai Jiang
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Abstract

Abnormalities in the Wnt pathway are major drivers of cancer. RNF43 loss-of-function mutations are frequently detected in aggressive cancers lacking targeted therapies, underscoring the need to uncover key regulators and targets of this pathway. Using a double death trap (DDT) Wnt reporter and genome-wide CRISPR screen, we identified STT3A as an essential regulator of Wnt signaling. Genetic and pharmacological inhibition of STT3A suppressed aberrant Wnt activity caused by RNF43/ZNRF3 loss. Importantly, suppression of STT3A blocked the growth of RNF43-deficient cancer cell lines, patient-derived organoids, and spontaneous tumors. Mechanistically, STT3A regulates Wnt/β-catenin signaling via LRP6, but not LRP5. Glycosylation of LRP6 by STT3A is required for Wnt ligand binding. Notably, STT3A depletion displayed milder effects on bone homeostasis, as supported by phenotypes in STT3A-deficient patients. Together, this study established STT3A as a critical Wnt regulator through LRP6 glycosylation and a therapeutic target for RNF43-deficient cancers.

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HumansWnt Signaling PathwayUbiquitin-Protein LigasesLow Density Lipoprotein Receptor-Related Protein-6AnimalsNeoplasmsMiceDNA-Binding ProteinsCell Line, TumorLRP6 glycosylationRNF43-deficient cancersSTT3AWnt signalingtherapeutic targetJournal ArticleResearch Support, Non-U.S. Gov't

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Zhengjin He, Shishuang Chen, Jinlong Suo, Kai Xia, Mingxian Liu, Jingchuan Ma, Yankai Chu, Chao Wang, Yueru Xie, Wei Jiang, Hui Du, Shiyang Chen, Zhilei Zhou, Man Li, Qing Wei, Yun Zhao, Jianfeng Chen, Lin Li, Yi Zeng, Weiguo Zou, Moubin Lin, Hai Jiang. 2025-10-22. STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency.. https://doi.org/10.1016/j.chembiol.2025.10.001

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